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An Antiviral Pill to Treat COVID?

— ZDoggMD shares what we know, and what we still need to determine, about molnupiravir

MedpageToday

Merck just announced promising early results for an oral therapeutic for outpatients with SARS-CoV-2. In this video, ZDoggMD explains what we know about molnupiravir so far, what we still need to learn, and what it could mean in the fight against COVID-19.

Following is a rough transcript (note that errors are possible):

ZDoggMD: Hey, guys. It's Dr. Z. I put a jacket on 'cause we're talking about Big Pharma, molnupiravir.

Molnupiravir. That's a mouthful. New antiviral medication, trial results out. The thing like cuts hospitalization risk in half in the trial that they did with Merck. So let's go through this real quick because many people realize that, hey, there are antibiotics that kill bacteria, we've had things that kill microorganisms for a long time, but antivirals, drugs that actually hurt viruses are much more rare. You think about in HIV, our medications that turned HIV from a death sentence into a chronic disease, really because we didn't have a good vaccine that could work there, and so that space we kind of understand antivirals a little bit.

Influenza, we have Tamiflu, the herpes, we've got acyclovir, valacyclovir, but that's really it. For COVID, we have remdesivir, which is kind of crap. Like even the WHO is like don't even use it. Maybe it reduces duration of illness, not clear that it stops people from dying, so really not a great armamentarium for treatments. Now people talk about ivermectin and all that, but until we see data that the thing actually works, you've seen my videos on that. All right. So, what is up with molnupiravir? So this is making the news now, and I think deservedly so, because here's a drug that actually has a mechanism of action that directly inhibits this virus.

So, here's kind of the history of it. It was, the drug was originally discovered at Emory at one of the nonprofits that Emory sets up to look at drug discovery, and it was originally looked at for influenza, for trying to fight flu, because what this drug does is, it's what they call a prodrug, so like when it gets metabolized in the body, it turns into a ribonucleoside analog. That's a fancy way of saying it pretends to be one of the components that viruses use with their RNA polymerase to actually replicate themselves and make new RNA for the new viral particles. So it turns out that the ribonucleoside that it makes really induces serious mutation in the virus.

So the virus tries to make a copy of itself, it uses these kinds of bogus particles that the drug induces, and the virus suffers what they call, just, catastrophic viral mutation. Now remember, a little bit of viral mutation happens all the time, that's how we get variants, but a lot of viral mutation means the virus can't even assemble itself. It's just a lethal mutation for the virus. So it mutates itself to death. So this drug molnupiravir actually induces this in coronavirus, and it was seen originally in some animal studies, because in 2019, they were ready to look at it for influenza. Then the pandemic happened and they said hey, it seems to have some effect in animal studies on coronavirus, so let's follow up, and they did. So, the trial that they were enrolling for, the goal of enrollment for the trial was something like 1,500, 1,800-odd people, but something quite remarkable happened.

So, they enrolled about 700-and-some-odd people and they started the trial, and it was global, all around the world, and the criteria for being in the trial were interesting. You had to have mild or moderate disease, not be hospitalized yet, and you had to have at least one risk factor for severe disease that put you at risk for ending up really sick, and that could be age, that could be obesity, heart disease, diabetes, things along that nature, and you, if you met those criteria, then you could be enrolled in the trial. So you had to have been sick for less than 5 days, and have a confirmed positive PCR test for coronavirus.

So here are people who are infected. They're not yet hospitalized, right. Now remember, we have other therapeutics for people like this. They're called monoclonal antibodies, things like Regeneron, etc, and so we do have that but the problem with those is they have to be given IV. It's a logistical nightmare for the patient and for the healthcare system because that's a very resource-intensive thing, but they are pretty effective, right. So here's a pill that you could take as an outpatient that is taken twice a day for like 5 days. That is a lot easier to do than monoclonals, right. And so this trial entity then, the group of people that were enrolled were told to do this, okay.

Either you get the pill twice a day for 5 days or you get a placebo pill, and then they compared and saw that happened, and this is, again, around the world. And it turns out, it's interesting because the circulating variants that they tested against were like 80% were Delta, Mu, and Gamma, so some pretty serious variants. So if you could knock these variants out, you're doing pretty good, right. And the other thing is these were unvaccinated people. So the population was unvaccinated. All right. So, what did they find? Well, it turns out about 7% of the group that got the drug ended up hospitalized. None of them died. About 14% of the placebo group ended up hospitalized, and eight of them died.

That means that's a 50% reduction in hospitalization, in a group of about 700-odd people. Half got placebo, half got the treatment. And nobody died in the treatment group, right. Not huge numbers, but still. It was powerful enough that an independent group that monitors these trials said you need to stop this trial, not because people are dying, not because there's something terrible, but because it's so effective that if you keep giving people placebo, it's unethical because you could be saving lives and preventing hospitalizations. The signal of efficacy was that strong in this trial. That's pretty impressive. When you consider that in the history of respiratory viruses, we don't have anything that's that powerful against respiratory viruses, I mean, there's really nothing that does that, it's pretty remarkable, right. So the trial got stopped. Merck announced their topline results, meaning here's the basic gist of what we can announce, but no one's seen the primary data yet.

They said, okay, in terms of side effects, there were no significant differences between placebo group and treatment group, and actually more people had to bail on the placebo group due to perceived side effects than in the treatment group, which is interesting. Barely, right, by like 1%. Now we need to see the actual data. And remember, there were no pregnant women in this trial. They were excluded as well. So we don't know if this thing causes birth defects, is safe in pregnancy, right, had not been looked at, that I know of. So, we don't think that it has big side effects but we don't know till we see the primary data, and we don't know its effect in populations outside of what was studied.

So, here's how we want to think about this, okay. This is how I formulate this. You now have a potential therapeutic that can actually cut hospitalizations in half in people at high risk. Here's what I'd love to see in a therapeutic. I'd love to see it actually stop the progression of disease. In this case, it appeared to do so when given early. Remember, hospitalized, severe patients, they were not in this trial, so we don't know what happens with them, all right. I would love to see it actually prevent something like long COVID. So if you're infected and you get better, you don't get hospitalized, but you still end up with symptoms at 6 months of headache, and cough, and shortness of breath, well that's not so much of a win, is it?

So I'd love to see that, so you need longer-term data on that. You need to look at that specifically as one of the outcome measures. And I'd love to see it actually prevent transmission, so if you give it to somebody, they're less likely to transmit the disease, so less viral load, less viral replication, less transmission. That would be great too. And the fourth thing I'd love to see is that you can give it not just to treat disease when you're known positive, but to contacts of people in their family, say, okay, dad came down with COVID, he's positive, he's taken this pill, great, can I take it too as a prophylactic, right, which you can do with things like Tamiflu.

So if that's the case, then you have a pretty strong case here for pretty much the end of the pandemic, because what you could say is well, vaccination, first of all, very important point. So does that mean that you don't need to vaccinate? Okay, that's just dumb. Shut your mouth. Preventing a disease is much better than having to treat it, all right, especially if this thing doesn't prevent long COVID and all that, and we just don't know enough, so vaccine, vaccine, vaccine, vaccine.

Okay, I've gotten that out of the way. The combination of vaccine and this. So let's say you have a breakthrough, you're a high-risk person, you break through the vaccine and now you have a small risk but still not zero of being hospitalized, you take molnupiravir. Does that lower the risk even further, right? Well this population wasn't vaccinated so we don't know.

It looks to be effective against variants. That's great. It has a mechanism of action that's really different, which means it's gonna be hard to overcome for the virus. You combine it with vaccination. You now have a population that should frickin' stop wearing masks, open up fully, stop talking about coronavirus, assuming this all works, right, if you're vaccinated, as many people as you can get vaccinated, get vaccinated, and then if they fail that, take molnupiravir, and if they fail that, then they're in the hospital getting dexamethasone, or maybe they've gotten molnupiravir and monoclonal antibodies, which again, they work in different parts of the spectrum here, so they could totally easily be given together.

Now you have a really powerful regimen to treat viral SARS-CoV-2. At that point, which is soon, I think, why are we even talking about this anymore? At this point between vaccination and the few people that are just super stubborn, they're never gonna get a vaccination or they've been naturally infected, they don't want to get a vaccination, even the one dose we're recommending, look, you have this thing, can we get back to our lives? Can we stop talking about coronavirus? Can we celebrate the scientific accomplishments here between the vaccinations and molnupiravir? And that's really interesting because this was a public-private thing.

Emory University developing originally, then Ridgeback Pharmaceuticals, partnering with Merck, then the government saying, you know what, we'll buy this many doses whether it works or not, taking some of the risk away. Man, that's how science ought to work, right? Then we gotta look, make sure what the side effects are, see what the deal is with pregnant people, continue to advocate vaccination and all that, and stop forcing colleges to mask kids who are vaccinated, having classes with all this spacing, not letting them eat together. Have we lost our minds, you guys? Like nobody just, nobody understands risk. Nobody understands risk, right.

And then you'll have therapeutics, you'll have vaccines, you'll have a way to manage people who are hospitalized. We have dexamethasone, remdesivir. We've learned a lot about this thing, right. Now, kids, pediatrics, this thing hasn't been studied in kids so we're gonna have to look at that. What's the deal with that? Kids in general are lower risk, but you do want to prevent COVID in them because you don't want to end up with, like, MIS-C or one of these unusual syndromes that happens. Vaccinations might be extended to kids, but I would really like to see the risk-benefit on that data, the full data before I would make a decision on my 10-year-old.

Okay, so that's how I think about molnupiravir therapeutics. I think that's the best that I can do at this point. As more information comes out, we'll be thinking about it more. In the meantime, just share this video. I put a suit on for you guys. There's no tie. I don't own a tie, but there's a suit, 'cause we're talking about Merck, all right. I love you guys so much. Share the video, and we are out. Peace.

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